Tumor-induced osteomalacia (TIO, or oncogenic osteomalacia) is an insidious, progressive, paraneoplastic disorder of abnormal phosphate and vitamin D metabolism caused by excessive fibroblast growth factor 23 (FGF23). Due to a lack of appreciation of the existence of this disease, as well as a typically slow onset of symptoms, the prevalence of TIO is most likely under-estimated. Chronically elevated FGF23 leads to renal phosphate wasting with resultant hypophosphatemia and phosphaturia, low vitamin D, and osteomalacia, with frequent fractures. Elevated FGF23 may also lead to a) secondary hyperparathyroidism (SHPT), b) renal osteodystrophy, c) extra-skeletal calcification, and d) left ventricular hypertrophy (Tomasello, 2008). Proteolytic cleavage of FGF23 produces a C-terminal peptide (FGF23c) that acts as an endogenous inhibitor of the fulllength, bioactive form of FGF23 to alleviate FGF23-mediated renal phosphate wasting (Goetz, 2010). To develop a best-in-class therapeutic based on this inhibitor, we will create a proteolytic antibody, FGF23- abzyme !iFGF23-abzl. iFGF23-abz is a binary weapon: a) directly binding and neutralizing FGF23, and b) releasing the inhibitory FGF23c to attenuate FGF23-mediated signaling and restore homeostasis. Based on recent successes of our group (Sharma, 2009) and others (Hifumi, 2012; Treweek, 2012) with design of proteolytic antibodies, iFGF23-abz carries a heavy chain to bind the amino-terminal domain of FGF23, and a proteolytic Ab light chain to release FGF23c. iFGF23-abz is expected to more efficiently restore homeostasis than a conventional inhibitory Ab or an FGF23c fusion protein. In Phase I, a conventional human anti-FGF23 antibody, FGF23c, and iFGF23-abz will be generated and compared using in vitro assays. Based on the outcome of these studies, the best molecule will be further developed in Phase II. Phase II will support expanded animal studies using renal phosphate wasting models, PK/PD, toxicology, and production optimization to support submission of an IND for this orphan indication. Other orphan indications of this therapy might include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), and fibrous dysplasia of bone.